Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools

Nara Liessi, Elena Cichero, Emanuela Pesce, Maria Arkel, Annalisa Salis, Valeria Tomati, Matteo Paccagnella, Gianluca Damonte, Bruno Tasso, Luis J.V. Galietta, Nicoletta Pedemonte, Paola Fossa, Enrico Millo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.

Original languageEnglish
Pages (from-to)179-200
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume144
DOIs
Publication statusPublished - Jan 20 2018

Fingerprint

Thiazoles
Quantitative Structure-Activity Relationship
Derivatives
Cystic Fibrosis Transmembrane Conductance Regulator
Molecules
Mutant Proteins
Cell membranes
Scaffolds
Proteolysis
Assays
Epithelial Cells
Cells
Cell Membrane
Degradation
Mutation
Processing
Proteins
lumacaftor

Keywords

  • Aminoarylthiazole
  • CFTR
  • Corrector
  • Cystic fibrosis
  • QSAR
  • VX809

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. / Liessi, Nara; Cichero, Elena; Pesce, Emanuela; Arkel, Maria; Salis, Annalisa; Tomati, Valeria; Paccagnella, Matteo; Damonte, Gianluca; Tasso, Bruno; Galietta, Luis J.V.; Pedemonte, Nicoletta; Fossa, Paola; Millo, Enrico.

In: European Journal of Medicinal Chemistry, Vol. 144, 20.01.2018, p. 179-200.

Research output: Contribution to journalArticle

Liessi, Nara ; Cichero, Elena ; Pesce, Emanuela ; Arkel, Maria ; Salis, Annalisa ; Tomati, Valeria ; Paccagnella, Matteo ; Damonte, Gianluca ; Tasso, Bruno ; Galietta, Luis J.V. ; Pedemonte, Nicoletta ; Fossa, Paola ; Millo, Enrico. / Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 144. pp. 179-200.
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